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Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma

Author

Listed:
  • Sarah A. Best

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Sheryl Ding

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Ariena Kersbergen

    (The Walter and Eliza Hall Institute of Medical Research)

  • Xueyi Dong

    (The University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Ji-Ying Song

    (The Netherlands Cancer Institute)

  • Yi Xie

    (The Walter and Eliza Hall Institute of Medical Research
    Fudan University)

  • Boris Reljic

    (The University of Melbourne)

  • Kaiming Li

    (The Walter and Eliza Hall Institute of Medical Research
    Nanjing University)

  • James E. Vince

    (The University of Melbourne
    The Walter and Eliza Hall Institute of Medical Research)

  • Vivek Rathi

    (The University of Melbourne)

  • Gavin M. Wright

    (The University of Melbourne)

  • Matthew E. Ritchie

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

  • Kate D. Sutherland

    (The Walter and Eliza Hall Institute of Medical Research
    The University of Melbourne)

Abstract

The KRAS oncoprotein, a critical driver in 33% of lung adenocarcinoma (LUAD), has remained an elusive clinical target due to its perceived undruggable nature. The identification of dependencies borne through common co-occurring mutations are sought to more effectively target KRAS-mutant lung cancer. Approximately 20% of KRAS-mutant LUAD carry loss-of-function mutations in KEAP1, a negative regulator of the antioxidant response transcription factor NFE2L2/NRF2. We demonstrate that Keap1-deficient KrasG12D lung tumors arise from a bronchiolar cell-of-origin, lacking pro-tumorigenic macrophages observed in tumors originating from alveolar cells. Keap1 loss activates the pentose phosphate pathway, inhibition of which, using 6-AN, abrogated tumor growth. These studies highlight alternative therapeutic approaches to specifically target this unique subset of KRAS-mutant LUAD cancers.

Suggested Citation

  • Sarah A. Best & Sheryl Ding & Ariena Kersbergen & Xueyi Dong & Ji-Ying Song & Yi Xie & Boris Reljic & Kaiming Li & James E. Vince & Vivek Rathi & Gavin M. Wright & Matthew E. Ritchie & Kate D. Sutherl, 2019. "Distinct initiating events underpin the immune and metabolic heterogeneity of KRAS-mutant lung adenocarcinoma," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12164-y
    DOI: 10.1038/s41467-019-12164-y
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